Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Mutation and/or overexpression of certain oncogenes is frequently associated with cellular tranformation and human cancer. To acquire transforming potential, the precursor of the ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as anticancer agents for tumors. Mutated, oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1934 to 1937, (1993)). Proteins other than ras may play a part in tumorigenicity and may also require farnesylation for biological activity.
International Patent Publication Number WO92/11034 (published Jul. 9, 1992) discloses a method of increasing the sensitivity of a tumor to an antineoplastic agent (in cases where the tumor is resistant to the antineoplastic agent), by the concurrent administration of the antineoplastic agent and (inter alia) a potentiating agent of the formula: ##STR1##
wherein the dotted line represents an optional double bond, X' is hydrogen or halo, and Y' is hydrogen, substituted carboxylate or substituted sulfonyl. For example, Y' can be, amongst others, --COOR' wherein R' is C-1 to C-6 alkyl or substituted alkyl, phenyl, substituted phenyl, C-7 to C-12 aralkyl or substituted aralkyl, 2-, 3- or 4-piperidyl or N-substituted piperidyl. Y' can also be, amongst others, SO.sub.2 R' wherein R' is C-1 to C-6 alkyl, phenyl, substituted phenyl, C-7 to C-12 aralkyl or substituted aralkyl. Examples of such potentiating agents include 11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines such as Loratadine. Antineoplastic agents exemplified are: vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B, emetine, maytansine, and amsacrine. The WO92/11034 publication focuses on potentiating the antineoplastic agents through a specific mechanism of action: inhibition of multiple drug resistance.
In view of the need for improved treatments for proliferative diseases, particularly cancers, novel methods of treatment would be a welcome contribution to the art. The present invention provides just such methods of treatment.